ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 20 citations in OpenAlex.
- A pan-cancer single-cell transcriptomic atlas of human bone metastases.Cell reports. Medicine · 2026Article
- Dual implication of endothelial adhesion molecules in tumor progression and cancer immunity.Cell adhesion & migration · 2025Review
- Building simplified cancer subtyping and prediction models with glycan gene signatures.Cell reports methods · 2025Article
- Decoding Metastasis: From Cell Death to Fusion in Cancer Progression.Current cancer drug targets · 2025Review
- Comparison of ex vivo bioluminescence imaging, Alu-qPCR and histology for the quantification of spontaneous lung and bone metastases in subcutaneous xenograft mouse models.Clinical & experimental metastasis · 2024Article
- EarlyFrontiers in oncology · 2024Article
- E-selectin in vascular pathophysiology.Frontiers in immunology · 2024Review
- Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria-related pathways in colorectal cancer.Molecular oncology · 2024Article
- Identification of potential classes of glycoligands mediating dynamic endothelial adhesion of human tumor cells.Glycobiology · 2023Article
- Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity.Cancers · 2022Review
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26 authors at 6 institutions in 2 countries.
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Abstract
Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.
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